The human tumor necrosis factor α (hTNF-α) is a multifunctional cytokine secreted by macrophage/monocyte and has wide spectrum of biological activity. It plays important roles in inflammatory reaction, immune regulation, tumor suppression, anti-microorganism and helminth infection. It also plays a central role in cytokine network. When suffering from inflammation, autoimmune disease, allergy, shock, the expression of TNF-α increases by hundreds of thousands to develop inflammation process and exacerbatethe disease. As TNF-α is an important virulence factor, it is closely involved in many autoimmune diseases, e.g., rheumatoid arthritis (RA), children multiple rheumatoid arthritis (JRA), pyremia, cardiac infarction, systemic lupus erythematosus (SLE) and diabetes. Therefore, antagonist of TNF-α is important for the treatment of these diseases (“Tumor Necrosis Factor Receptor Family Members in the Immune System”, Immunology, 1998, 10:423˜434).
There are many TNF blockade for the treatment of the diseases mentioned above (referring to “Treatment of Rheumatoid Arthritis: New Therapeutic Approaches with Biological Agents”, Curr Durg Targets Immune Endocr Metabol Disord, 2001 May; 1 (1): 45-65). For example, Infliximid, (Avakine; ReMicade) manufactured by Johnson & Johnson Ltd., U.S.A. for treating rheumatoid arthritis, and Crohn's disease has already been available in market since November 1998. Infliximide is a chimeric antibody against hTNF-α. The Etemercept (Embrel; Enbrel) for treating rheumatoid arthritis and Crohn's disease, manufactured by Immunex Ltd., U.S.A. has already been available in market since December 1998. Etemercept is a fusion protein of the IgG1 Fc domain and the TNF receptor p75 (Etanerecept in rheumatoid arthritis. Expert Opin Pharmacother, 2001, 2(7):1137˜1148) (Psoriatic Arthritis: The Role of TNF Inhibition and The Effect of its Inhibition with Etanercept. Clin Exp Rheumatol. 2002 November-December; 20(6 Supple 28): S116-21). Although these protein drugs provide good therapeutic effect, there are still disadvantages. First, the process of protein preparation is complicated and expensive; secondly, the protein drug has high molecular weight, very difficult to get to the target tissues because of its poor permeability; thirdly, the blood clearance is so low that it is difficult to excrete, which results in its accumulation in the body and causes side effect; finally, due to the introduction of the exogenous proteins and the change of structure, the proteins have immunogenicity, once repeatedly used, it induces antibody formation. The polypeptide with low molecular weight has good pharmacokinetic characteristics and strong capability of tissue permeability, however, the target molecule is unavailable and the molecule has low affinity, which limits the clinical application (referring to “What Are the Risks of Biologic Therapy in Rheumatoid Arthritis? An Update on Safety by J. Rheumatol, Suppl. 2002 September; 65:33-8).